Research output per year
Research output per year
Rebecca B. Delconte, Tatiana B Kolesnik, Laura F. Dagley, Jai Rautela, Wei Shi, Eva M. Putz, Kimberley Stannard, Jian Guo Zhang, Charis En-Yi Teh, Matt Firth, Takashi Ushiki, Christopher E Andoniou, Mariapia A Degli-Esposti, Phillip P Sharp, Caroline E. Sanvitale, Giuseppe Infusini, Nicholas P.D. Liau, Edmond M Linossi, Christopher J Burns, Sebastian Carotta
Research output: Contribution to journal › Article › Research › peer-review
The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish -/- mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.
Original language | English |
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Pages (from-to) | 816-824 |
Number of pages | 9 |
Journal | Nature Immunology |
Volume | 17 |
Issue number | 7 |
DOIs | |
Publication status | Published - 21 Jun 2016 |
Research output: Contribution to journal › Comment / Debate › Other › peer-review
National Health and Medical Research Council (NHMRC) (Australia)
1/01/09 → 31/10/16
Project: Research